Quinoline derivatives as nk-2 and nk-3 receptor antagonists

ABSTRACT

Compounds of the formula (I) are disclosed which are NK2 and NK3 receptor antagonists and are useful in the treatment of respiratory diseases:  
                 
or a pharmaceutically acceptable salt thereof.

FIELD OF THE INVENTION

The present invention relates to novel compounds, in particular to novelquinoline derivatives, to processes for the preparation of suchcompounds, to pharmaceutical compositions containing such compounds andto the use of such compounds in medicine.

BACKGROUND OF THE INVENTION

The mammalian peptide Neurokinin B (NKB) belongs to the Tachykinin (TK)peptide family which also include Substance P(SP) and Neurokinin A(NKA). Pharmacological and molecular biological evidence has shown theexistence of three subtypes of TK receptor (NK₁, NK₂ and NK₃) and NKBbinds preferentially to the NK₃ receptor although it also recognizes theother two receptors with lower affinity (Maggi et al, 1993, J. Auton.Pharmacol., 13, 23-93).

Selective peptidic NK₃ receptor antagonists are known (Drapeau, 1990Regul. Pept., 31, 125-135), and findings with peptidic NK₃ receptoragonists suggest that NKB, by activating the NK₃ receptor, has a keyrole in the modulation of neural input in airways, skin, spinal cord andnigro-striatal pathways (Myers and Undem, 1993, J. Physiol., 470,665-679; Counture et al., 1993, Regul. Peptides, 46, 426-429; Mccarsonand Krause, 1994, J. Neurosci., 14 (2), 712-720; Arenas et al. 1991, J.Neurosci., 11, 2332-8). However, the peptide-like nature of the knownantagonists makes them likely to be too labile from a metabolic point ofview to serve as practical therapeutic agents.

International Patent Application, Publication Number WO 00/58307describes a series of aryl fused 2,4-disubstituted pyridines, such asnaphthyridine derivatives, which are stated to exhibit biologicalactivity as NK₃ receptor antagonists.

The compounds of the present invention are quinoline derivatives. Otherquinoline derivatives have been described previously as selective NK₃antagonists. For example, International Patent Application, PublicationNumbers, WO 95/32948 and WO 96/02509 describe a series of selective andpotent NK₃ receptor antagonists.

International Patent Application, Publication Number WO 00/64877describes a series of 2-aminoquinolinecarboxamides as neurokininreceptor ligands.

International Patent Application, Publication Number, WO 00/58303describes a series of 4-substituted quinoline derivatives which arestated to be NK₃ and/or GABA(A) receptor ligands. Such compounds arecharacterized by the presence of a nitrogen-containing heterocyclicmoiety at the C(4) position of the quinoline ring.

International Patent Application, Publication Numbers, WO 97/21680, WO98/52942, WO 00/31037, WO 00/31038, WO 02/38547, WO 02/38548, WO02/43734, WO 02/44154, and WO 02/44165 describe compounds which havebiological activity as combined NK₃ and NK₂ receptor antagonists.

We have now discovered a further novel class of non-peptide NK₃antagonists which are far more stable from a metabolic point of viewthan the known peptidic NK₃ receptor antagonists and are of potentialtherapeutic utility. These compounds also have NK₂ antagonist activityand are therefore considered to be of potential use in the preventionand treatment of a wide variety of clinical conditions, which arecharacterised by overstimulation of the Tachykinin receptors, inparticular NK₃ and NK₂.

These conditions include respiratory diseases, such as chronicobstructive pulmonary disease (COPD), asthma, airway hyper-reactivity,cough; inflammatory diseases such as inflammatory bowel disease,psoriasis, fibrositis, osteoarthritis, rheumatoid arthritis andinflammatory pain; neurogenic inflammation or peripheral neuropathy,allergies such as eczema and rhinitis; ophthalmic diseases such asocular inflammation, conjunctivitis, vernal conjuctivitis and the like;cutaneous diseases, skin disorders and itch, such as cutaneous wheal andflare, contact dermatitis, atopic dermatitis, urticaria and othereczematoid dermatitis; adverse immunological reactions such as rejectionof transplanted tissues and disorders related to immune enhancement orsuppression such as systhemic lupus erythematosis; gastrointestinal (GI)disorders and diseases of the GI tract such as disorders associated withthe neuronal control of viscera such as ulcerative colitis, Crohn'sdisease, irritable bowel syndrome (IBS), gastro-exophageous reflexdisease (GERD); urinary incontinence and disorders of the bladderfunction; renal disorders; increased blood pressure, proteinuria,coagulopathy and peripheral and cerebral oedema following pre-eclampsiain pregnancies (hereinafter referred to as the ‘Primary Conditions’).

Certain of these compounds also show CNS activity and hence areconsidered to be of particular use in the treatment of disorders of thecentral nervous system such as anxiety, depression, psychosis andschizophrenia; neurodegenerative disorders such as AIDS relateddementia, senile dementia of the Alzheimer type, Alzheimer's disease,Down's syndrome, Huntingdon's disease, Parkinson's disease, movementdisorders and convulsive disorders (for example epilepsy); demyelinatingdiseases such as multiple sclerosis and amyotrophic lateral sclerosisand other neuropathological disorders such as diabetic neuropathy, AIDSrelated neuropathy, chemotherapy-induced neuropathy and neuralgia;addiction disorders such as alcoholism; stress related somaticdisorders; reflex sympathetic dystrophy such as shoulder/hand syndrome;dysthymic disorders; eating disorders (such as food intake disease);fibrosing and collagen diseases such as scleroderma and eosinophilicfascioliasis; disorders of the blood flow caused by vasodilatation andvasospastic diseases such as angina, migraine and Reynaud's disease andpain or nociception, for example, that is attributable to or associatedwith any of the foregoing conditions especially the transmission of painin migraine, (hereinafter referred to as the ‘Secondary Conditions’).

The compounds of formula (I) are also considered to be useful asdiagnostic tools for assessing the degree to which neurokinin-3 andneurokinin-2 receptor activity (normal, overactivity or underactivity)is implicated in a patient's symptoms.

Certain compounds of the present invention have also been found toexhibit surprisingly advantageous pharmacochemical properties.

DETAILED DESCRIPTION OF THE INVENTION

According to the present invention, there is provided a compound offormula (I) below or a pharmaceutically acceptable salt or solvatethereof:

wherein:R₁ is H or substituted or unsubstituted (C₁₋₆)alkyl;R₂ is substituted or unsubstituted aryl, (C₃₋₇)cycloalkyl, orheterocycle;R₃ is H or substituted or unsubstituted (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl,aryl or heterocycle;A is NR₈ or O;R₈ is H or substituted or unsubstituted (C₁₋₆)alkyl;R₄ is substituted or unsubstituted heterocycle;R₅ is H or up to three substitutents independently selected from thelist consisting of alkyl, alkenyl, aryl, alkoxy, or a hydroxylatedderiviative thereof, hydroxy, halogen, nitro, cyano, carboxy,alkylcarboxy, alkylcarboxyalkyl, haloalkyl, amino or mono- ordialkylamino; or R₅ represents a bridging moiety which is arranged tobridge two adjacent ring atoms wherein the bridging moiety comprisesalkyl or dioxyalkylene;R₆ is H or halo;R₇ is oxo;n is 1 to 4.Preferably, R₁ is methyl.Suitably, R₂ is substituted or unsubstituted aryl or (C₃₋₇)cycloalkyl.Preferably, R₂ is substituted or unsubstituted phenyl or cyclohexyl.Most preferably R₂ is unsubstituted phenyl or cyclohexyl.Preferably R₃ is (C₁₋₆)alkyl or heterocycle. Methyl is a most perferredR₃ group. Other most preferred R₃ groups are substituted andunsubstituted morpholino, piperizine, pyrrole, piperidine, thiophene,imidazole, and pyrazole.Preferably R₈ is H or methyl.Preferably R₄ is substituted or unsubstituted 2-thienyl or 3-thienyl.Most preferably R4 is unsubstituted 2-thienyl or 3-thienyl.Preferably R₅ is H or fluoro.Preferably R₆ is H or fluoro.Preferably n is 1.

Preferred compounds of formula (I) which are of special interest asagents useful in the treatment and/or prophylaxis of conditions whichare characterised by overstimulation of the Tachykinin receptors, inparticular NK₃ and NK₂, are:

-   3-(4-Dimethylcarbamoylmethyl-3-oxo-piperazin-1-ylmethyl)-2-thiophen-2-yl-quinoline-4-carboxylic    acid ((S)-1-cyclohexyl-ethyl)-amide,-   3-[4-(2-Morpholin-4-yl-2-oxo-ethyl)-3-oxo-piperazin-1-ylmethyl)-2-thiophen-2-yl-quinoline-4-carboxylic    acid ((S)-1-cyclohexyl-ethyl)-amide,-   3-[3-Oxo-4-(2-oxo-2-piperazin-1-yl-ethyl)-piperazin-1-ylmethyl)-2-thiophen-2-yl-quinoline-4-carboxylic    acid ((S)-1-cyclohexyl-ethyl)-amide,-   3-(4-Carbamoylmethyl-3-oxo-piperazin-1-ylmethyl)-2-thiophen-2-yl-quinoline-4-carboxylic    acid ((S)-1-cyclohexyl-ethyl)-amide,-   3-{4-[2-(4-Methyl-piperazin-1-yl)-2-oxo-ethyl]-3-oxo-piperazin-1-ylmethyl}-2-thiophen-2-yl-quinoline-4-carboxylic    acid ((S)-1-cyclohexyl-ethyl)-amide,-   3-[3-Oxo-4-(2-oxo-piperidin-1-yl-ethyl)-piperazin-1    ylmethyl]-2-thiophen-2-yl-quinoline-4-carboxylic acid    ((S)-1-cyclohexyl-ethyl)-amide,-   3-[3-Oxo-4-(2-oxo-pyrrolidin-1-yl-ethyl)-piperazin-1    ylmethyl]-2-thiophen-2-yl-quinoline-4-carboxylic acid    ((S)-1-cyclohexyl-ethyl)-amide,-   3-[4-(3-Morpholin-4-yl-3-oxo-propyl)-3-oxo-piperazin-1-ylmethyl)-2-thiophen-2-yl-quinoline-4-carboxylic    acid ((S)-1-cyclohexyl-ethyl)-amide,-   3-(4-(2-Morpholin-4-yl-2-oxo-ethyl)-2-oxo-piperazin-1-ylmethyl]-2-thiophen-2-yl-quinoline-4-carboxylic    acid ((S)-1-cyclohexyl-ethyl)-amide,-   3-(4-Dimethylcarbamoylmethyl-2-oxo-piperazin-1-ylmethyl)-2-thiophen-2-yl-quinoline-4-carboxylic    acid ((S)-1-cyclohexyl-ethyl)-amide,-   6-Fluoro-3-[4-(2-morpholin-4-yl-2-oxo-ethyl)-3-oxo-piperazin-1-ylmethyl]-2-thiophen-2-yl-quinoline-4-carboxylic    acid ((S)-1-cyclohexyl-ethyl)-amide,-   6-Fluoro-3-[3-oxo-4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperazin-1-ylmethyl]-2-thiophen-2-yl-quinoline-4-carboxylic    acid ((S)-1-cyclohexyl-ethyl)-amide,-   3-{4-[2-((R)-2-Hydroxymethyl-pyrrolidin-1-yl)-2-oxo-ethyl]-3-oxo-piperazin-1-ylmethyl}-2-thiophen-2′-yl-quinoline-4-carboxylic    acid ((S)-1-cyclohexyl-ethyl)-amide,-   3-(4-{[(2,5-Dimethyl-2H-pyrazol-3ylmethyl)-carbamoyl]-methyl}-3-oxo-piperazin-1-ylmethyl)-2-thiophen-2-yl-quinoline-4-carboxylic    acid ((S)-1-cyclohexyl-ethyl)-amide,-   3-(4-{[(5-Methyl-1H-imidazol-2ylmethyl)-carbamoyl]-methyl}-3-oxo-piperazin-1-ylmethyl)-2-thiophen-2-yl-quinoline-4-carboxylic    acid ((S)-1-cyclohexyl-ethyl)-amide, and-   3-{4-[(Methyl-thiophen-2ylmethyl)-carbamoyl)-methyl}-3-oxo-piperazin-1-ylmethyl)-2-thiophen-2-yl-quinoline-4-carboxylic    acid ((S)-1-cyclohexyl-ethyl)-amide, or a pharmaceutically    acceptable salt thereof.

The compounds of formula (I) may have at least one asymmetric centre—forexample the carbon atom labelled with an asterisk (*) in the compound offormula (I)—and therefore may exist in more than one stereoisomericform. The invention extends to all such stereoisomeric forms and tomixtures thereof, including racemates. In particular, the inventionincludes compounds wherein the asterisked carbon atom in formula (I) hasthe stereochemistry shown in formula (Ib):

wherein R₁, R₂, R₄, R₅, and R₆ are as defined in relation to formula(I), and X represents the moiety

wherein R₇ and R₃ are as defined in relation to formula (I).

The compounds of formula (I) or their salts or solvates are preferablyin pharmaceutically acceptable or substantially pure form. Bypharmaceutically acceptable form is meant, inter alia, having apharmaceutically acceptable level of purity excluding normalpharmaceutical additives such as diluents and carriers, and including nomaterial considered toxic at normal dosage levels.

A substantially pure form will generally contain at least 50% (excludingnormal pharmaceutical additives), preferably 75%, more preferably 90%and still more preferably 95% of the compound of formula (I) or its saltor solvate.

One preferred pharmaceutically acceptable form is the crystalline form,including such form in pharmaceutical composition. In the case of saltsand solvates the additional ionic and solvent moieties must also benon-toxic.

Suitable salts are pharmaceutically acceptable salts.

Suitable pharmaceutically acceptable salts include the acid additionsalts with the conventional pharmaceutical acids, for example maleic,hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic,citric, lactic, mandelic, tartaric, succinic, benzoic, ascorbic andmethanesulphonic.

Suitable pharmaceutically acceptable salts include salts of acidicmoieties of the compounds of formula (I) when they are present, forexample salts of carboxy groups or phenolic hydroxy groups.

Suitable salts of acidic moieties include metal salts, such as forexample aluminium, alkali metal salts such as lithium, sodium orpotassium, alkaline earth metal salts such as calcium or magnesium andammonium or substituted ammonium salts, for example those with loweralkylamines such as triethylamine, hydroxy alkylamines such as2-hydroxyethylamine, bis-(2-hydroxyethyl)-amine ortri-(2-hydroxyethyl)-amine, cycloalkylamines such as bicyclohexylamine,or with procaine, dibenzylpiperidine, N-benzyl-β-phenethylamine,dehydroabietylamine, N,N′-bisdehydroabietylamine, glucamine,N-methylglucamine or bases of the pyridine type such as pyridine,collidine, quinine or quinoline.

Suitable solvates are pharmaceutically acceptable solvates.

Suitable pharmaceutically acceptable solvates include hydrates.

The term ‘alkyl’ or (C₁₋₆)alkyl (unless specified to the contrary) whenused alone or when forming part of other groups (such as the ‘alkoxy’group) includes straight- or branched-chain alkyl groups containing 1 to6 carbon atoms, examples include methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl or tert-butyl group.

The term ‘alkenyl’ or (C₁₋₆)alkenyl (unless specified to the contrary)when used alone or when forming part of other groups includes straight-or branched-unsaturated carbon chains including at least one double C═Cbond and containing 2-6 carbon atoms.

The term ‘carbocylic’ refers to cycloalkyl and aryl rings.

The term ‘cycloalkyl’ includes groups having 3 to 7 ring carbon atoms.

Suitable substituents for any (C₁₋₆)alkyl, (C₁₋₆)alkenyl, or(C₃₋₇)cycloalkyl group include up to three substituents selected fromthe group consisting of hydroxy, halogen, nitro, cycano, carboxy, amino,mono- and di-(C₁₋₆)alkylamino carboxamido, sulphonamido,(C₁₋₆)alkoxycarbonyl, trifluromethyl, acyloxy, aryl, heterocycle, and(C₃₋₇)cycloalkyl.

The term ‘aryl’ includes phenyl and naphthyl, preferably phenyl whichunless specified to the contrary optionally comprise up to five,preferably up to three substituents selected from halogen, alkyl,phenyl, alkoxy, haloalkyl, hydroxyalkyl, hydroxy, amino, nitro, cyano,carboxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkylcarbonyloxy, oralkylcarbonyl groups.

The term ‘aromatic heterocyclic group’ includes groups comprisingaromatic heterocyclic rings containing from 5 to 12 ring atoms, suitably5 or 6, and comprising up to four hetero-atoms in the or each ringselected from S, O or N.

Composite terms such as ‘alkylcarboxy’, ‘cycloalkylalkyl’ and so forthrefer to components of a compound which include two interlinked groups,with the group named latterly in the term being the linking group, sothat ‘alkylcarboxy’ means (alkyl)-COO— whilst ‘cycloalkylalkyl’ means(cycloalkyl)-(alkyl)-.

Unless specified to the contrary, suitable substituents for anyheterocyclic group includes up to 4 substituents selected from the groupconsisting of: alkyl, alkoxy, aryl and halogen or any two substituentson adjacent carbon atoms, together with the carbon atoms to which theyare attached, may form an aryl group, preferably a benzene ring, andwherein the carbon atoms of the aryl group represented by the said twosubstituents may themselves be substituted or unsubstituted.

When used herein the term “halogen” refers to fluorine, chlorine,bromine and iodine, preferably fluorine, chlorine or bromine.

When used herein the term “acyl” includes residues of acids, inparticular a residue of a carboxylic acid such as an alkyl oraryl-carbonyl group.

Certain reagents are abbreviated herein. DCC refers todicyclohexylcarbodiimide, DMAP refers to dimethylaminopyridine, DIEArefers to diisopropylethyl amine, EDC refers to1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, hydrochloride. HOBtrefers to 1-hydroxybenzotriazole, THF refers to tetrahydrofuran, DIEArefers to diisopropylethylamine, DEAD refers to diethylazodicarboxylate, PPh₃ refers to triphenylphosphine, DIAD refers todiisopropyl azodicarboxylate, DME refers to dimethoxyethane, DMF refersto dimethylformamide, NBS refers to N-bromosuccinimide, Pd/C refers to apalladium on carbon catalyst, PPA refers to polyphosphoric acid, DPPArefers to diphenylphosphoryl azide, BOP refers tobenzotriazol-1-yloxy-tris(dimethyl-amino)phosphoniumhexafluorophosphate, HF refers to hydrofluoric acid, TEA refers totriethylamine, TFA refers to trifluoroacetic acid, PCC refers topyridinium chlorochromate.

The invention also provides in one aspect a process for the preparationof a compound of formula (I), or a salt thereof and/or a solvatethereof, which process comprises reacting a compound of formula (II) oran active derivative thereof:

wherein R′₄, R′₅, R′₆ and X′ are R₄, R₅, R₆ and X respectively ashereinbefore defined in relation to formula (I) or (Ib), or a groupconvertible to R₄, R₅, R₆ and X respectively; with a compound of formula(III):

wherein R′₁ and R′₂ are R₁ and R₂ as defined for formula (I) or a groupor atom convertible to R₁ and R₂ respectively; to form a compound offormula (Ic):

wherein R′₁, R′₂, X′, R′₄, R′₅ and R′₆ are as defined above, andthereafter carrying out one or more of the following optional steps:(i) converting any one of R′₁, R′₂, X′, R′₄, R′₅ and R′₆ to R₁, R₂, X,R₄, R₅ and R₆ respectively as required, to obtain a compound of formula(I);(ii) converting a compound of formula (I) into another compound offormula (I); and(iii) preparing a salt of the compound of formula (I) and/or a solvatethereof.

Suitable groups convertible into other groups include protected forms ofsaid groups.

Suitably R′₁, R′₂, X′, R′₄, R′₅ and R′₆ each represents R₁, R₂, X, R₄,R₅ and R₆ respectively or a protected form thereof.

It is favoured if the compound of formula (II) is present as an activederivative.

A suitable active derivative of a compound of formula (II) is atransient activated form of the compound of formula (II) or a derivativewherein the carboxy group of the compound of formula (II) has beenreplaced by a different group or atom, for example by an acyl halide,preferably a chloride, or an acylazide or a carboxylic acid anhydride.

Other suitable active derivatives include: a mixed anhydride formedbetween the carboxyl moiety of the compound of formula (II) and an alkylchloroformate; an activated ester, such as a cyanomethyl ester,thiophenyl ester, p-nitrophenyl ester, p-nitrothiophenyl ester,2,4,6-trichlorophenyl ester, pentachlorophenyl ester, pentafluorophenylester, N-hydroxy-phtalimido ester, N-hydroxypiperidine ester,N-hydroxysuccinimide ester, N-hydroxy benzotriazole ester;alternatively, the carboxy group of the compound of formula (II) may beactivated using a carbodiimide or N,N′-carbonyldiimidazole.

The reaction between the compound of formula (II) or the activederivative thereof and the compound of formula (III) is carried outunder the appropriate conventional conditions for the particularcompounds chosen. Generally, when the compound of formula (II) ispresent as an active derivative the reaction is carried out using thesame solvent and conditions as used to prepare the active derivative,preferably the active derivative is prepared in situ prior to formingthe compound of formula (Ic) and thereafter the compound of formula (I)or a salt thereof and/or a solvate thereof is prepared.

For example, the reaction between an active derivative of the compoundof formula (II) and the compound of formula (III) may be carried out:

(a) by first preparing an acid chloride and then coupling said chloridewith the compound of formula (III) in the presence of an inorganic ororganic base in a suitable aprotic solvent such as dimethylformamide(DMF) at a temperature in a range from −70 to 50° C. (preferably in arange from −10 to 20° C.); or

(b) by treating the compound of formula (II) with a compound of formula(III) in the presence of a suitable condensing agent, such as forexample N,N′-carbonyl diimidazole (CDI) or a carbodiimide such asdicyclohexylcarbodiimide (DCC) orN-dimethylaminopropyl-N′-ethylcarbodiimide, preferably in the presenceof N-hydroxybenzotriazole (HOBT) to maximise yields and avoidracemization processes (see Synthesis, 453, 1972), orO-benzotriazol-1-yl-N,N,N′,N′-tetramethyluroniumhexafluorophosphate(HBTU), in an aprotic solvent, such as a mixture of acetonitrile (MeCN)and tetrahydrofuran (THF), for example a mixture in a volume ratio offrom 1:9 to 7:3 (MeCN:THF), at any temperature providing a suitable rateof formation of the required product, such as a temperature in the rangeof from −70 to 50° C., preferably in a range of from −10 to 25° C., forexample at 0° C.

A preferred reaction is set out in Scheme 1 shown below:

wherein R′₁, R′₂, X′, R′₄, R′₅ and R′₆ are as defined above.

In the case in which the corresponding alkyl (such as methyl or ethyl)ester of compound (II) is utilised, an hydrolysis to compound (II) isrequired before conversion to compound (Ic) in Scheme 1. Such hydrolysiscan be carried out under acidic conditions, such 10-36% hydrochloricacid at a temperature in the range between 30 and 100° C.

It will be appreciated that a compound of formula (Ic) may be convertedto a compound of formula (I), or one compound of formula (I) may beconverted to another compound of formula (I) by interconversion ofsuitable substituents. Thus, certain compounds of formula (I) and (Ic)are useful intermediates in forming other compounds of the presentinvention.

Accordingly, in a further aspect the invention provides a process forpreparing a compound of formula (I), or a salt thereof and/or a solvatethereof, which process comprises converting a compound of the abovedefined formula (Ic) wherein at least one of R′₁, R′₂, X′, R′₄, R′₅ andR′₆ is not R₁, R₂, X, R₄, R₅ or R₆ respectively, thereby to provide acompound of formula (I); and thereafter, as required, carrying out oneor more of the following optional steps:

(i) converting a compound of formula (I) into another compound offormula (I); and

(ii) preparing a salt of the compound of formula (I) and/or a solvatethereof.

Suitably, in the compound of formula (Ic) the variables R′₁, R′₂, X′,R′₄, R′₅ and R′₆ are R₁, R₂, X, R₄, R₅ and R₆ respectively or they areprotected forms thereof.

The above mentioned conversions, protections and deprotections arecarried out using the appropriate conventional reagents and conditionsand are further discussed below.

A chiral compound of formula (III) wherein R₂ is a C₅ or C₇ cycloalkylgroup, R₃ is methyl and R₁ is H are described in J. Org. Chem. (1996),61 (12), 4130-4135. A chiral compound of formula (III) wherein R₂ isphenyl, R₃ is isopropyl and R₁ is H is a known compound described in forexample Tetrahedron Lett. (1994), 35(22), 3745-6.

The compounds of formula (III) are known commercially availablecompounds or they can be prepared from known compounds by known methods,or methods analogous to those used to prepare known compounds, forexample the methods described in Liebigs Ann. der Chemie, (1936), 523,199.

In some embodiments of the invention, a compound of formula (II) or thecorresponding alkyl (such as methyl or ethyl) ester is prepared byreacting a compound of formula (IV) or the corresponding alkyl (such asmethyl or ethyl) ester:

wherein R′₄, R′₅ and R′₆ are as defined above and L₁ represents ahalogen atom such as a bromine atom, with a compound of formula (V):

wherein R₃ and R₇ are as defined in relation to formula (I) or aprotected form thereof.

Suitably, reaction between the compounds of formulae (IV) or thecorresponding alkyl (such as methyl or ethyl) ester and (V) is carriedout under conventional amination conditions, for example when L₁ is abromine atom then the reaction is conveniently carried out in an aproticsolvent, such as tetrahydrofuran or dimethylformamide at any temperatureproviding a suitable rate of formation of the required product, usuallyat ambient temperature; preferably the reaction is carried out in thepresence of triethylamine (TEA) or K₂CO₃.

The compounds of formula (V) are known, commercially available compoundsor they can be prepared using methods analogous to those used to prepareknown compounds; for example the methods described in the Chemistry ofthe Amino Group, Patais (Ed.), Interscience, New York 1968; AdvancedOrganic Chemistry, March J, John Wiley & Sons, New York, 1992; J.Heterocyclic Chem. (1990), 27, 1559; Synthesis (1975), 135, Bioorg. Med.Chem. Lett. (1997), 7, 555, or Protective Groups in Organic Synthesis(second edition), Wiley Interscience, (1991) or other methods mentionedherein.

A compound of formula (IV) or the corresponding alkyl (such as methyl orethyl) ester may be prepared by appropriate halogenation of a compoundof formula (VI) or the corresponding alkyl (such as methyl or ethyl)ester:

wherein R′₄, R′₅ and R′₆ are as defined above in relation to formula(II).

Suitable halogenation reagents are conventional reagents depending uponthe nature of the halogen atom required, for example when L₁ is brominea preferred halogenation reagent is N-bromosuccinimide (NBS).

The halogenation of the compound of formula (VI) or the correspondingalkyl (such as methyl or ethyl) ester is suitably carried out underconventional conditions, for example bromination is carried out bytreatment with NBS in an inert solvent, such as carbon tetrachlorideCCl₄, or 1,2-dichloroethane or CH₃CN, at any temperature providing asuitable rate of formation of the required product, suitably at anelevated temperature such as a temperature in the range of 60° C. to100° C., for example 80° C.; preferably the reaction is carried out inthe presence of a catalytic amount of benzoyl peroxide.

A compound of formula (VI) is conveniently prepared by reacting acompound of formula (VII):

wherein R′₅ and R′₆ are as defined in relation to formula (II), with acompound of formula (XIII):R₄′—CO—CH₂—Me  (XII)

wherein R′₄ is as defined in relation to formula (II).

The reaction between the compounds of formula (VII) and (XIII) isconveniently carried out using Pfitzinger reaction conditions (see forexample J. Prakt. Chem. 33, 100 (1886), J. Prakt. Chem. 38, 582 (1888),J. Chem. Soc. 106 (1948) and Chem. Rev. 35, 152 (1944)). For example inan alkanolic solvent such as ethanol, at any temperature providing asuitable rate of formation of the required product, but generally at anelevated temperature, such as the reflux temperature of the solvent, andpreferably in the presence of a base such as potassium hydroxide orpotassium tert-butoxide. The Pfitzinger reaction may also be carried outin presence of an acid, such as acetic acid or hydrochloric acid, at atemperature providing a suitable rate of formation of the requiredproduct, but generally at an elevated temperature, as described in J.Med. Chem. 38, 906 (1995).

The compounds of formula (VII) are known compounds or they are preparedaccording to methods used to prepare known compounds for example thosedisclosed in J. Org. Chem. 21, 171 (1955); J. Org. Chem. 21, 169 (1955).

Alternatively a compound of formula (VI) may be conveniently prepared byreacting a compound of formula (XIV)

wherein R′₅ and R′₆ are as defined in relation to formula (II), with acompound of formula (XV):R₄′—CHO  (XV)

wherein R′₄ is as defined in relation to formula (II) in presence ofoxobutyric acid.

The reaction between the compounds of formula (XIV) and (XV) isconveniently carried out using Doebner reaction conditions (see forexample Chem. Ber. 29, 352 (1894); Chem. Revs. 35, 153, (1944); J. Chem.Soc. B, 1969, 805), for example in an alcoholic solvent such as ethanol,at any temperature providing a suitable rate of formation of therequired product, but generally at an elevated temperature, such as thereflux temperature of the solvent.

The compounds of formula (XIV) and (XV) are known compounds or they areprepared according to methods used to prepare known compounds forexample as described in Vogel's Textbook of Practical Organic Chemistry.

In some alternative embodiments of the invention, a compound of formula(II) is prepared by reacting a compound of formula (VII) as definedabove with a compound of formula (VIII):R₄′—CO—CH₂—CH₂-T₅  (VIII)

wherein R′₄ is as defined in relation to formula (II), and T₅ is a group

where Y is a protecting group such as a benzyl group, particularly aprotecting group which is stable in basic conditions such as aterbutoxycarbonyl group; and thereafter as required removing anyprotecting group, for example by dehydrogenation, and/or converting anyT₅ group to:

The reaction between the compounds of formula (VII) and (VIII) isconveniently carried out using Pfitzinger reaction conditions (see forexample J. Prakt. Chem. 33, 100 (1886), J. Prakt. Chem. 38, 582 (1888),J. Chem. Soc. 106 (1948) and Chem. Rev. 35, 152 (1944)), for example inan alkanolic solvent such as ethanol, at any temperature providing asuitable rate of formation of the required product, but generally at anelevated temperature, such as the reflux temperature of the solvent, andpreferably in the presence of a base such as potassium hydroxide orpotassium tert-butoxide.

Protected forms of,

will vary according to the particular nature of the group beingprotected but will be chosen in accordance with normal chemicalpractice.

Groups convertible to,

include groups dictated by conventional chemical practice to be requiredand to be appropriate, depending upon the specific nature of the groupunder consideration.

Suitable deprotection methods for deprotecting protected forms of

and conversion methods for converting T₅ to,

will be those used conventionally in the art depending upon theparticular groups under consideration with reference to standard textssuch as Greene, T. W. and Wuts, P. G. M. Protective Groups in OrganicSynthesis, John Wiley & Sons Inc. New York, 1991 (Second Edt.) or inKocienski, P. J. Protecting groups. George Thieme Verlag, New York, 1994and Chemistry of the Amino Group, Patais (Ed.), Interscience, New York1968; or Advanced Organic Chemistry, March J, John Wiley & Sons, NewYork, 1992.

A compound of formula (VIII) is prepared from a compound of formula(IX):R₄′—CO—CH₂—CH₂—OH  (IX)

wherein R′₅ is as defined in relation to formula (II), by firsthalogenating, preferably brominating, or mesylating the compound offormula (IX) and thereafter reacting the halogenation or mesylationproduct so formed with a compound capable of forming a group T₅ so as toprovide the required compound of formula (VII).

When T₅ is a group,

a compound capable of forming a group T₅ is a compound of the abovedefined formula (V).

The halogenation of the compound of formula (IX) is suitably carried outusing a conventional halogenation reagent. Mesylation is convenientlycarried out using mesyl chloride in an inert solvent such as methylenedichloride, at a temperature below room temperature, such as 0° C.,preferably in the presence of triethylamine.

The reaction conditions between the compound of formula (IX) and thecompound capable of forming a group T₅ will be those conventionalconditions dictated by the specific nature of the reactants, for examplewhen the T₅ required is a group,

and the required compound capable of forming a group T₅ is a compound ofthe above defined formula (V), then the reaction between thehalogenation or mesylation product of the compound of formula (IX) andthe compound of formula (V) is carried out under analogous conditions tothose described for the reaction between the compounds of formulae (IV)and (V).

Other compounds capable of forming a group T₅ will depend upon theparticular nature of T₅, but will be those appropriate compoundsdictated by conventional chemical practice with reference to standardtexts such as Chemistry of the Amino Group, Patais (Ed.), Interscience,New York 1968; and Advanced Organic Chemistry, March J, John Wiley &Sons, New York, 1992.

A compound of formula (IX) may be prepared by reacting a compound offormula (X):

wherein a is as defined in relation to formula (VIII), with a lithiumsalt of formula (XI):R′₅Li  (XI)wherein R′₅ is as defined in relation to formula (II).

The reaction between the compounds of formulae (X) and (XI) can becarried out in an aprotic solvent, such as diethyl-ether at anytemperature providing a suitable rate of formation of the requiredproduct, usually at a low temperature such as in the range of −10° C. to−30° C., for example −20° C.

The compounds of formula (VII) are known compounds or they are preparedaccording to methods used to prepare known compounds for example thosedisclosed in J. Org. Chem. 21, 171 (1955); J. Org. Chem. 21, 169 (1955).

The compounds of formula (X) and (XI) are known compounds or they areprepared according to methods used to prepare known compounds forexample those disclosed by Krow G. R. in Organic Reactions, Vol 43, page251, John Wiley & Sons Inc. 1994 (for the compounds of formula (X)) andOrganometallics in Synthesis, Schlosser M. (Ed), John Wiley & Sons Inc.1994 (for the compounds of formula (XI)).

In another aspect, the present invention provides a process for thepreparation of a compound of formula (I), or a salt thereof and/or asolvate thereof, which process comprises reacting a compound of formula(XVI):

wherein each of R′₁, R′₂, R′₄, R′₅, and R′₆ is respectively R₁, R₂, R₄,R₅, or R₆ as defined above or a group convertible to R₁, R₂, R₄, R₅, orR₆ respectively as defined above providing R′₂ is not aromatic incharacter, and L₁ represents a halogen atom such as a bromine atom, witha compound of formula (V) or a protected form thereof or a groupconvertible thereto; and thereafter carrying out one or more of thefollowing optional steps:(i) converting any one of R′₁, R′₂, R′₃, R′₄, R′₅, and R′₆ to R₁, R₂,R₃, R₄, R₅, and R₆ respectively as required, to obtain a compound offormula (I);(ii) converting a compound of formula (I) into another compound offormula (I); and(iii) preparing a salt of the compound of formula (I) and/or a solvatethereof.

Protected forms of compounds of formula (V) will vary according to theparticular nature of the group being protected but will be chosen inaccordance with normal chemical practice.

Groups convertible to R₃ include groups dictated by conventionalchemical practice to be required and to be appropriate, depending uponthe specific nature of the R₃ under consideration.

Suitable deprotection methods for deprotecting protected forms of R₃ andconversion methods for converting R′₃ to R₃ will be those usedconventionally in the art depending upon the particular groups underconsideration with reference to standard texts such as Greene, T. W. andWuts, P. G. M. Protective Groups in Organic Synthesis, John Wiley & SonsInc. New York, 1991 (Second Edt.) or in Kocienski, P. J. Protectinggroups. George Thieme Verlag, New York, 1994 and Chemistry of the AminoGroup, Patais (Ed.), Interscience, New York 1968; or Advanced OrganicChemistry, March J, John Wiley & Sons, New York, 1992.

Suitable groups convertible into other groups include protected forms ofsaid groups.

Suitably R′₁, R′₂, R′₃, R′₄, R′₅, and R′₆ each represents R₁, R₂, R₃,R₄, R₅, and R₆ respectively or a protected form thereof.

Suitable deprotection methods for deprotecting protected forms of R₁,R₂, R₃, R₄, R₅, and R₆ and conversion methods for converting R′₁, R′₂,R′₃, R′₄, R′₅, and R′₆ to R₁, R₂, R₃, R₄, R₅, and R₆ respectively willbe those used conventionally in the art depending upon the particulargroups under consideration with reference to standard texts such asGreene, T. W. and Wuts, P. G. M. Protective Groups in Organic Synthesis,John Wiley & Sons Inc. New York, 1991 (Second Edt.) or in Kocienski, P.J. Protecting groups. George Thieme Verlag, New York, 1994 and Chemistryof the Amino Group, Patais (Ed.), Interscience, New York 1968; orAdvanced Organic Chemistry, March J, John Wiley & Sons, New York, 1992.

Suitably, reaction between the compounds of formulae (XVI) and (XVII) iscarried out under conventional amination conditions, for example when L₁is a bromine atom then the reaction is conveniently carried out in anaprotic solvent, such as tetrahydrofuran or dimethylformamide oracetonitrile at any temperature providing a suitable rate of formationof the required product, usually at ambient temperature; preferably thereaction is carried out in the presence of triethylamine (TEA), sodiumhydride or K₂CO₃.

The compounds of formula (XVII) are known, commercially availablecompounds or they can be prepared using methods analogous to those usedto prepare known compounds; for example the methods described in theChemistry of the Amino Group, Patais (Ed.), Interscience, New York 1968;Advanced Organic Chemistry, March J, John Wiley & Sons, New York, 1992;J. Heterocyclic Chem. (1990), 27, 1559; Synthesis (1975), 135, Bioorg.Med. Chem. Lett. (1997), 7, 555, or Protective Groups in OrganicSynthesis (second edition), Wiley Interscience, (1991) or other methodsmentioned herein.

A compound of formula (XVI) is prepared by appropriate halogenation of acompound of formula (XVIII):

wherein R′₁, R′₂, R′₄, R′₅, and R′₆ are as defined above in relation toformula (XVI).

Suitable halogenation reagents are conventional reagents depending uponthe nature of the halogen atom required, for example when L₁ is brominea preferred halogenation reagent is N-bromosuccinimide (NBS).

The halogenation of the compound of formula (XVIII) is carried out underconventional conditions, for example bromination is carried out bytreatment with NBS in an inert solvent, such as carbon tetrachlorideCCl₄, or 1,2-dichloroethane or CH₃CN, at any temperature providing asuitable rate of formation of the required product, suitably at anelevated temperature such as a temperature in the range of 60° C. to100° C., for example 80° C.; preferably the reaction is carried out inthe presence of a catalytic amount of benzoyl peroxide.

Suitably, the compound of formula (XVIII) may be prepared by reacting acompound of formula (VI) as defined above or an active derivativethereof with a compound of formula (III) as defined above wherein R′₂ isnot aromatic in character.

It is favoured if the compound of formula (VI) is present in thereaction mix as an active derivative, as hereinbefore described.

The reaction between the compound of formula (VI) or the activederivative thereof and the compound of formula (III) is carried outunder the appropriate conventional conditions for the particularcompounds chosen. Generally, when the compound of formula (VI) ispresent as an active derivative the reaction is carried out using thesame solvent and conditions as used to prepare the active derivative,preferably the active derivative is prepared in situ prior to formingthe compound of formula (XVIII).

For example, the reaction between an active derivative of the compoundof formula (VI) and the compound of formula (III) may be carried out:

(a) by first preparing an acid chloride and then coupling said chloridewith the compound of formula (III) in the presence of an inorganic ororganic base in a suitable aprotic solvent such as methylene dichlorideor tetrahydrofuran at a temperature in a range from −70 to 50° C.(preferably in a range from 20° C. to reflux temperature); or

(b) by treating the compound of formula (VI) with a compound of formula(III) in the presence of a suitable condensing agent, such as forexample N,N′-carbonyl diimidazole (CDI) or a carbodiimide such asdicyclohexylcarbodiimide (DCC) orN-dimethylaminopropyl-N′-ethylcarbodiimide, preferably in the presenceof N-hydroxybenzotriazole (HOBT) to maximise yields and avoidracemization processes (see Synthesis, 453, 1972), orO-benzotriazol-1-yl-N,N,N′,N′-tetramethyluroniumhexafluorophosphate(HBTU), in an aprotic solvent, such as a mixture of acetonitrile (MeCN)and tetrahydrofuran (THF), for example a mixture in a volume ratio offrom 1:9 to 7:3 (MeCN:THF), at any temperature providing a suitable rateof formation of the required product, such as a temperature in the rangeof from −70 to 50° C., preferably in a range of from −10 to 25° C., forexample at 0° C.

A preferred reaction is set out in Scheme 2 shown below:

In the case in which the corresponding alkyl (such as methyl or ethyl)ester of compounds (VI) is utilised, a hydrolysis is required beforeconversion to compound (XVIII) in Scheme 2. Such hydrolysis can becarried out under acidic conditions, such 10-36% hydrochloric acid at atemperature in the range between 30 and 100° C.

As hereinbefore mentioned, the compounds of formula (I) may exist inmore than one stereoisomeric form—and the process of the invention mayproduce racemates as well as enantiomerically pure forms. Accordingly, apure enantiomer of a compound of formula (I) can be obtained by reactinga compound of the above defined formula (II) with an appropriateenantiomerically pure primary anine of formula (IIIa) or (IIIc):

wherein R′₁, and R′₂ are as defined above, to obtain a compound offormula (I′a) or (I′c):

wherein R′₁, R′₂, X′, R′₄, R′₅, and R′₆ are as defined above.

Compounds of formula (I′a) or (I′c) may subsequently be converted tocompounds of formula (Ia) or (Ic) by the methods of conversion mentionedbefore:

wherein R₁, R₂, X, R₄, R₅, and R₆ are as defined above.

An alternative method for separating optical isomers is to useconventional, fractional separation methods in particular fractionalcrystallization methods. Thus, a pure enantiomer of a compound offormula (I) is obtained by fractional crystallisation of adiastereomeric salt formed by reaction of the racemic compound offormula (I) with an optically active strong acid resolving agent, suchas camphosulphonic acid, tartaric acid, O,O′-di-p-toluoyltartaric acidor mandelic acid, in an appropriate alcoholic solvent, such as ethanolor methanol, or in a ketonic solvent, such as acetone. The saltformation process should be conducted at a temperature between 20° C.and 80° C., preferably at 50° C.

A suitable conversion of one compound of formula (I) into a furthercompound of formula (I) involves converting one group X into anothergroup X by for example:

(i) converting a ketal into a ketone, by such as mild acidic hydrolysis,using for example dilute hydrochloric acid;

(ii) reducing a ketone to a hydroxy group by use of a borohydridereducing agent;

(iii) converting a carboxylic ester group into a carboxyl group usingbasic hydrolysis; and/or

(iv) reducing a carboxylic ester group to a hydroxymethyl group, by useof a borohydride reducing agent.

As indicated above, where necessary, the conversion of any group R′₁,R′₂, X′, R′₄, R′₅, and R′₆ into R₁, R₂, X, R₄, R₅, and R₆ which asstated above are usually protected forms of R₁, R₂, X, R₄, R₅, or R₆ maybe carried out using appropriate conventional conditions such as theappropriate deprotection procedure.

It will be appreciated that in any of the above mentioned reactions anyreactive group in the substrate molecule may be protected anddeprotected according to conventional chemical practice, for example asdescribed by Greene, T. W. and Wuts, P. G. M. Protective Groups inOrganic Synthesis, John Wiley & Sons Inc. New York, 1991 (Second Edt.)or in Kocienski, P. J. Protecting groups. George Thieme Verlag, NewYork, 1994.

Suitable protecting groups in any of the above mentioned reactions arethose used conventionally in the art. Thus, for example suitable hydroxyprotecting groups include benzyl or trialkylsilyl groups.

The methods of formation and removal of such protecting groups are thoseconventional methods appropriate to the molecule being protected. Thusfor example a benzyloxy group may be prepared by treatment of theappropriate compound with a benzyl halide, such as benzyl bromide, andthereafter, if required, the benzyl group may be conveniently removedusing catalytic hydrogenation or a mild ether cleavage reagent such astrimethylsilyl iodide or boron tribromide.

The compounds of the present invention were prepared by the methodsillustrated in Schemes III and IV.

Reagents and Conditions: a) KOH, EtOH; b) i) Oxallyl chloride, DMF(cat.) CH₂Cl₂; ii) (S)-Cyclohexylethylamine, triethylamine, CH₂Cl₂; c)NBS, dibenzoyl peroxide, CCl₄; d) 2-oxo-piperazine,N,N-diisopropylethylamine, CH₃CN; e) NaH, Bromoacetic acid ethyl ester,DMF, 18 hrs., then, LiOH, MeOH/water; f) Dimethylamine, HBTU,4-methylmorpholine, DMF.

Thus, reaction of 1-(2-thienyl)-1-propanone with isatin under basicconditions yields the desired carboxylic acid III-3. Conversion to theacid chloride followed by reaction with R-(−)-1-cyclohexylethylamineproduces amide II-4. This in turn is converted to3-(3-oxo-piperazin-1-ylmethyl)-2-thiophen-2-yl-quinoline-4-carboxylicacid ((S)-1-cyclohexyl-ethyl)-amide (III-6) (WO0244165) via the two stepprocedure of free radical bromination followed by S_(N)2 displacementwith piperazin-2-one. Reaction of intermediate III-6 with sodium hydridefollowed by bromoacetic acid ethylester in DMF produces the intermediateester. This is subsequently hydrolyzed to the acid in the same pot viatreatment with lithium hydroxide in methanol/water (1:1) to produce acidIII-7. Coupling of this acid with dimethylamine is accomplished withHBTU and 4-methylmorpholine in DMF yielding the desired amide III-8.

Alternatively, compounds of formula (I) may be prepared in a fashionanalogous to that depicted in Scheme IV.

a) NaH, 3-oxo-piperazine-1-carboxylic acid tert-butylester, DMF/DMSO(5/1), 0° C.; b) HCl, dioxane; c) N,N-diisopropyl ethylamine,bromoacetic acid ethylester; d) LiOH, EtOH, e) Morpholine, HBTU,4-methylmorpholine, DMF.

Thus, S_(N)2 displacement of the quinolinyl bromide with3-oxo-piperazine-1-carboxylic acid tert-butyl ester under basicconditions affords BOC carbamate IV-5. Removal of the BOC protectinggroup under acidic conditions followed by reaction of the product aminewith bromoacetic acid ethylester in the presence of Hunig's base affordsester IV-7. The ester may be hydrolyzed under basic conditions followedby coupling of the product acid with morpholine in the presence of HBTUand 4-methylmorpholine yielding the desired amide IV-9.

As indicated above, the compounds of formula (I) have usefulpharmaceutical properties.

Accordingly the present invention also provides a compound of formula(I), or a pharmaceutically acceptable salt or solvate thereof, for useas an active therapeutic substance.

In particular, the present invention also provides a compound of formula(I), or a pharmaceutically acceptable salt or solvate thereof, for thetreatment or prophylaxis of the Primary and Secondary Conditions.

The present invention further provides a pharmaceutical compositioncomprising a compound of formula (I), or a pharmaceutically acceptablesalt or solvate thereof, and a pharmaceutically acceptable carrier.

The present invention also provides the use of a compound of formula(I), or a pharmaceutically acceptable salt or solvate thereof, in themanufacture of a medicament for the treatment of the Primary andSecondary Conditions.

As mentioned abvove the Primary conditions include respiratory diseases,such as chronic obstructive pulmonary disease (COPD), asthma, airwayhyperreactivity, cough; inflammatory diseases such as inflammatory boweldisease, psoriasis, fibrositis, osteoarthritis, rheumatoid arthritis andinflammatory pain; neurogenic inflammation or peripheral neuropathy,allergies such as eczema and rhinitis; ophthalmic diseases such asocular inflammation, conjunctivitis, vernal conjuctivitis and the like;cutaneous diseases, skin disorders and itch, such as cutaneous wheal andflare, contact dermatitis, atopic dermatitis, urticaria and othereczematoid dermatitis; adverse immunological reactions such as rejectionof transplanted tissues and disorders related to immune enhancement orsuppression such as systhemic lupus erythematosis; gastrointestinal (GI)disorders and diseases of the GI tract such as disorders associated withthe neuronal control of viscera such as ulcerative colitis, Crohn'sdisease, irritable bowel syndrome (IBS), gastro-exophageous reflexdisease (GERD); urinary incontinence and disorders of the bladderfunction; renal disorders.

As mentioned abvove, the Secondary conditions disorders of the centralnervous system such as anxiety, depression, psychosis and schizophrenia;neurodegenerative disorders such as AIDS related dementia, seniledementia of the Alzheimer type, Alzheimer's disease, Down's syndrome,Huntington's disease, Parkinson's disease, movement disorders andconvulsive disorders (for example epilepsy); demyelinating diseases suchas multiple sclerosis and amyotrophic lateral sclerosis and otherneuropathological disorders such as diabetic neuropathy, AIDS relatedneuropathy, chemotherapy-induced neuropathy and neuralgia; addictiondisorders such as alcoholism; stress related somatic disorders; reflexsympathetic dystrophy such as shoulder/hand syndrome; dysthymicdisorders; eating disorders (such as food intake disease); fibrosing andcollagen diseases such as scleroderma and eosinophilic fascioliasis;disorders of the blood flow caused by vasodilation and vasospasticdiseases such as angina, migraine and Reynaud's disease and pain ornociception, for example, that is attributable to or associated with anyof the foregoing conditions especially the transmission of pain inmigraine.

Such a medicament, and a composition of this invention, may be preparedby admixture of a compound of the invention with an appropriate carrier.It may contain a diluent, binder, filler, disintegrant, flavouringagent, colouring agent, lubricant or preservative in conventionalmanner.

These conventional excipients may be employed for example as in thepreparation of compositions of known agents for treating the conditions.

Preferably, a pharmaceutical composition of the invention is in unitdosage form and in a form adapted for use in the medical or veterinarialfields. For example, such preparations may be in a pack form accompaniedby written or printed instructions for use as an agent in the treatmentof the conditions.

The suitable dosage range for the compounds of the invention depends onthe compound to be employed and on the condition of the patient. It willalso depend, inter alia, upon the relation of potency to absorbabilityand the frequency and route of administration.

The compound or composition of the invention may be formulated foradministration by any route, and is preferably in unit dosage form or ina form that a human patient may administer to himself in a singledosage. Advantageously, the composition is suitable for oral, rectal,topical, parenteral, intravenous or intramuscular administration.Preparations may be designed to give slow release of the activeingredient.

Compositions may, for example, be in the form of tablets, capsules,sachets, vials, powders, granules, lozenges, reconstitutable powders, orliquid preparations, for example solutions or suspensions, orsuppositories.

The compositions, for example those suitable for oral administration,may contain conventional excipients such as binding agents, for examplesyrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone;fillers, for example lactose, sugar, maize-starch, calcium phosphate,sorbitol or glycine; tabletting lubricants, for example magnesiumstearate; disintegrants, for example starch, polyvinyl-pyrrolidone,sodium starch glycollate or microcrystalline cellulose; orpharmaceutically acceptable setting agents such as sodium laurylsulphate.

Solid compositions may be obtained by conventional methods of blending,filling, tabletting or the like. Repeated blending operations may beused to distribute the active agent throughout those compositionsemploying large quantities of fillers. When the composition is in theform of a tablet, powder, or lozenge, any carrier suitable forformulating solid pharmaceutical compositions may be used, examplesbeing magnesium stearate, starch, glucose, lactose, sucrose, rice flourand chalk. Tablets may be coated according to methods well known innormal pharmaceutical practice, in particular with an enteric coating.The composition may also be in the form of an ingestible capsule, forexample of gelatin containing the compound, if desired with a carrier orother excipients.

Compositions for oral administration as liquids may be in the form of,for example, emulsions, syrups, or elixirs, or may be presented as a dryproduct for reconstitution with water or other suitable vehicle beforeuse. Such liquid compositions may contain conventional additives such assuspending agents, for example sorbitol, syrup, methyl cellulose,gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminiumstearate gel, hydrogenated edible fats; emulsifying agents, for examplelecithin, sorbitan monooleate, or acacia; aqueous or non-aqueousvehicles, which include edible oils, for example almond oil,fractionated coconut oil, oily esters, for example esters of glycerine,or propylene glycol, or ethyl alcohol, glycerine, water or normalsaline; preservatives, for example methyl or propyl p-hydroxybenzoate orsorbic acid; and if desired conventional flavouring or colouring agents.

The compounds of this invention may also be administered by a non-oralroute. In accordance with routine pharmaceutical procedure, thecompositions may be formulated, for example for rectal administration asa suppository. They may also be formulated for presentation in aninjectable form in an aqueous or non-aqueous solution, suspension oremulsion in a pharmaceutically acceptable liquid, e.g. sterilepyrogen-free water or a parenterally acceptable oil or a mixture ofliquids. The liquid may contain bacteriostatic agents, anti-oxidants orother preservatives, buffers or solutes to render the solution isotonicwith the blood, thickening agents, suspending agents or otherpharmaceutically acceptable additives. Such forms will be presented inunit dose form such as ampoules or disposable injection devices or inmulti-dose forms such as a bottle from which the appropriate dose may bewithdrawn or a solid form or concentrate which can be used to prepare aninjectable formulation.

The compounds of this invention may also be administered by inhalation,via the nasal or oral routes. Such administration can be carried outwith a spray formulation comprising a compound of the invention and asuitable carrier, optionally suspended in, for example, a hydrocarbonpropellant.

Preferred spray formulations comprise micronised compound particles incombination with a surfactant, solvent or a dispersing agent to preventthe sedimentation of suspended particles. Preferably, the compoundparticle size is from about 2 to 10 microns.

A further mode of administration of the compounds of the inventioncomprises transdermal delivery utilising a skin-patch formulation. Apreferred formulation comprises a compound of the invention dispersed ina pressure sensitive adhesive which adheres to the skin, therebypermitting the compound to diffuse from the adhesive through the skinfor delivery to the patient. For a constant rate of percutaneousabsorption, pressure sensitive adhesives known in the art such asnatural rubber or silicone can be used.

As mentioned above, the effective dose of compound depends on theparticular compound employed, the condition of the patient and on thefrequency and route of administration. A unit dose will generallycontain from 20 to 1000 mg and preferably will contain from 30 to 500mg, in particular 50, 100, 150, 200, 250, 300, 350, 400, 450, or 500 mg.The composition may be administered once or more times a day for example2, 3 or 4 times daily, and the total daily dose for a 70 kg adult willnormally be in the range 100 to 3000 mg. Alternatively the unit dosewill contain from 2 to 20 mg of active ingredient and be administered inmultiples, if desired, to give the preceding daily dose.

No unacceptable toxicological effects are expected with compounds of theinvention when administered in accordance with the invention.

The present invention also provides a method for the treatment and/orprophylaxis of the Primary and Secondary Conditions in mammals,particularly humans, which comprises administering to the mammal in needof such treatment and/or prophylaxis an effective, non-toxicpharmaceutically acceptable amount of a compound of formula (I) or apharmaceutically acceptable salt or solvate thereof.

The activity of the compounds of the present invention, as NK₃ ligands,is determined by their ability to inhibit the binding of theradiolabelled NK₃ ligands, [¹²⁵I]-[Me-Phe⁷]-NKB or [³H]-Senktide, toguinea-pig and human NK₃ receptors (Renzetti et al, 1991, Neuropeptide,18, 104-114; Buell et al, 1992, FEBS, 299(1), 90-95; Chung et al, 1994,Biochem. Biophys. Res. Commun., 198(3), 967-972).

The binding assays utilized allow the determination of the concentrationof the individual compound required to reduce by 50% the[¹²⁵I]-[Me-Phe⁷]-NKB and [³H]-Senktide specific binding to NK₃ receptorin equilibrium conditions (IC50).

Binding assays provide for each compound tested a mean IC₅₀ value of 2-5separate experiments performed in duplicate or triplicate. The mostpotent compounds of the present invention show IC₅₀ values in the range10-1000 nM. The NK₃-antagonist activity of the compounds of the presentinvention is determined by their ability to inhibit senktide-inducedcontraction of the guinea-pig ileum (Maggi et al, 1990, Br. J.Pharmacol., 101, 996-1000) and rabbit isolated iris sphincter muscle(Hall et al., 1991, Eur. J. Pharmacol., 199, 9-14) and human NK₃receptors-mediated Ca⁺⁺ mobilization (Mochizuki et al, 1994, J. Biol.Chem., 269, 9651-9658). Guinea-pig and rabbit in-vitro functional assaysprovide for each compound tested a mean K_(B) value of 3-8 separateexperiments, where K_(B) is the concentration of the individual compoundrequired to produce a 2-fold rightward shift in theconcentration-response curve of senktide. Human receptor functionalassay allows the determination of the concentration of the individualcompound required to reduce by 50% (IC₅₀ values) the Ca⁺⁺ mobilizationinduced by the agonist NKB. In this assay, the compounds of the presentinvention behave as antagonists.

The activity of the compounds of the present invention, as NK-2 ligands,is determined by their ability to inhibit the binding of theradiolabelled NK-2 ligands, [¹²⁵I]-NKA or [³H]-NKA, to human NK-2receptors (Aharony et al, 1992, Neuropeptide, 23, 121-130).

The binding assays utilized allow the determination of the concentrationof the individual compound required to reduce by 50% the [¹²⁵I]-NKA and[³H]-NKA specific binding to NK-2 receptor in equilibrium conditions(IC₅₀).

Binding assays provide for each compound tested a mean IC₅₀ value of 2-5separate experiments performed in duplicate or triplicate. The mostpotent compounds of the present invention show IC₅₀ values in the range1-1000 nM, such as 1-100 nM. The NK-2-antagonist activity of thecompounds of the present invention is determined by their ability toinhibit human NK-2 receptor-mediated Ca⁺⁺ mobilization (Mochizuki et al,1994, J. Biol. Chem., 269, 9651-9658). Human receptor functional assayallows the determination of the concentration of the individual compoundrequired to reduce by 50% (IC₅₀ values) the Ca⁺⁺ mobilization induced bythe agonist NKA. In this assay, the compounds of the present inventionbehave as antagonists.

The therapeutic potential of the compounds of the present invention intreating the conditions can be assessed using rodent disease models.

As stated above, the compounds of formula (I) are also considered to beuseful as diagnostic tool. Accordingly, the invention includes acompound of formula (I) for use as diagnostic tools for assessing thedegree to which neurokinin-2 and neurokinin-3 receptor activity (normal,overactivity or underactivity) is implicated in a patient's symptoms.Such use comprises the use of a compound of formula (I) as an antagonistof said activity, for example including but not restricted to tachykininagonist-induced inositol phosphate turnover or electrophysiologicalactivation, of a cell sample obtained from a patient. Comparison of suchactivity in the presence or absence of a compound of formula (I), willdisclose the degree of NK-2 and NK-3 receptor involvement in themediation of agonist effects in that tissue.

DESCRIPTIONS AND EXAMPLES

Nuclear magnetic resonance spectra were recorded at 400 MHz using aBruker AC 400 spectrometer. CDCl₃ is deuteriochloroform, DMSO-d₆ ishexadeuteriodimethylsulfoxide, and CD₃OD is tetradeuteriomethanol.Chemical shifts are reported in parts per million (δ) downfield from theinternal standard tetramethylsilane. Abbreviations for NMR data are asfollows: s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet,dd=doublet of doublets, dt=doublet of triplets, app=apparent, br=broad.J indicates the NMR coupling constant measured in Hertz. Continuous waveinfrared (IR) spectra were recorded on a Perkin-Elmer 683 infraredspectrometer, and Fourier transform infrared (FTIR) spectra wererecorded on a Nicolet Impact 400 D infrared spectrometer. IR and FTIRspectra were recorded in transmission mode, and band positions arereported in inverse wavenumbers (cm⁻¹). Mass spectra were taken oneither VG 70 FE, PE Syx API III, or VG ZAB HF instruments, using fastatom bombardment (FAB) or electrospray (ES) ionization techniques.Elemental analyses were obtained using a Perkin-Elmer 240C elementalanalyzer. Melting points were taken on a Thomas-Hoover melting pointapparatus and are uncorrected. All temperatures are reported in degreesCelsius.

Analtech Silica Gel GF and E. Merck Silica Gel 60 F-254 thin layerplates were used for thin layer chromatography. Both flash and gravitychromatography were carried out on E. Merck Kieselgel 60 (230-400 mesh)silica gel.

EXAMPLES

In the following synthetic examples, temperature is in degreesCentigrade (° C.). Unless otherwise indicated, all of the startingmaterials were obtained from commercial sources. For reverse phase HPLC(unless otherwise stated), a 50×20 mm I. D. YMC CombiPrep ODS-A columnat 20 mL/min with a 10 min gradient from 10% CH₃CN to 90% CH₃CN in H₂Owas used with a 2 min hold at 90% CH₃CN in H₂O at the end of each run.Without further elaboration, it is believed that one skilled in the artcan, using the preceding description, utilize the present invention toits fullest extent. These Examples are given to illustrate theinvention, not to limit its scope. Reference is made to the claims forwhat is reserved to the inventors hereunder.

Example 13-(4-Dimethylcarbamoylmethyl-3-oxo-piperazin-1-ylmethyl)-2-thiophen-2-yl-quinoline-4-carboxylicacid ((S)-1-cyclohexyl-ethyl)-amide 1a)3-Bromomethyl-2-thiophen-2-yl-quinoline-4-carboxylic acid,(S)-(1-cyclohexylethyl)amide

Methyl-2-thiophen-2-yl-quinoline-4-carboxylic acid,(S)-(1-cyclohexyl-ethyl)amide 10 g (0.0265 mol) and N-bromosuccinimide9.4 g (0.0528 mol) were suspended in rapidly stirringcarbontetrachloride (350 mL). The mixture was warmed to 80° C. in a hotwater bath after which time dibenzoyl peroxide (1.28 g, 0.0053 mol) wasadded in one portion. The mixture was heated at reflux for 30 minutesthen cooled rapidly in an ice bath. The resulting suspension wasfiltered and the filtrate concentrated under reduced pressure. Theresulting residue was taken into ethyl acetate and washed with saturatedsodium bicarbonate solution, water, brine, and dried over sodiumsulfate. Removal of the solvent under reduced pressure provided thecrude material which was used in the next step without furtherpurification.

1b)3-(3-oxo-piperazin-1-ylmethyl)-2-thiophen-2-yl-quinoline-4-carboxylicacid (S)-(1-cyclohexyl-ethyl)-amide

A solution of 3-Bromomethyl-2-thiophen-2-yl-quinoline-4-carboxylic acid,(S)-(1-cyclohexylethyl)amide (Example 1c), 2-oxo-piperazine (2.64 g,26.4 mmol) and diisopropylethyl amine (9.2 mL, 52.8 mmol) was kept atroom temperature overnight. The solution was evaporated to dryness andthe resulting residue purified by silica gel chromatography (gradient—80EtOAc/20 Hexanes/2 TEA to 100 EtOAc/2 TEA;). The product containingfractions were combined and concentrated and the resulting solidrecrystallized from dichloroethane. The remaining impurity was removedvia silica gel chromatography (gradient—70 EtOAc/30 Hexanes/2 TEA to 100EtOAc/2 TEA to give 1.8 g of pure product. MS (m/z) 477 M+.

1c){4-[4-((S)-1-Cyclohexyl-ethylcarbamoyl)-2-thiophen-2-yl-quinolin-3-ylmethyl]-2-oxo-piperazin-1-yl}-aceticacid

A mixture of3-(3-oxo-piperazin-1-ylmethyl)-2-thiophen-2-yl-quinoline-4-carboxylicacid ((S)-1-cyclohexyl-ethyl)-amide (1.5 g, 3.14 mmol) and sodiumhydride (0.19 g, 7.86 mmol) in 10 mL of DMF was stirred for 10 min at 0°C. Bromo acetic acid ethyl ester (0.35 mL, 3.14 mmol) was then added,and the resultant mixture stirred for an additional 18 hours at ambienttemperature. A mixture of lithium hydroxide (100 mg) in 2 mL of methanoland water (1:1) was then added to the reaction mixture. After stirringfor 18 hours, the suspension was filtered and the filtrate concentratedto yield the crude product. Purification via reverse phase HPLC, elutingwith acetonitrile/water/0.1% TFA (10/90, v/v to 90/10, v/v, over 10min), gave the desired product (1.54 g, 92%). MS (m/z) 535.2 (M⁺), 1.84min.

1d)3-(4-Dimethylcarbamoylmethyl-3-oxo-piperazin-1-ylmethyl)-2-thiophen-2-yl-quinoline-4-carboxylicacid ((S)-1-cyclohexyl-ethyl)-amide

To a solution of{4-[4-((S)-1-Cyclohexyl-ethylcarbamoyl)-2-thiophen-2-yl-quinolin-3-ylmethyl]-2-oxo-piperazin-1-yl}-aceticacid (Example 1c, 100 mg, 0.19 mmol) in 1.0 mL of DMF, dimethylamine(0.14 mL, 0.29 mmol), HBTU (110 mg, 0.29 mmol) and 4-methylmorpholine(63 μl, 0.57 mmol) were added. After the reaction mixture was stirred atroom temperature for 18 hours, it was partitioned between ethyl acetateand water. The combined organic phase was washed with water, brine,dried over MgSO₄, filtered and concentrated. Purification via reversephase HPLC, eluting with acetonitrile/water (10/90, v/v to 90/10, v/v,over 10 min), gave the desired product (67 mg, 63%).

MS (m/z) 562.0 (M⁺), 1.97 min.

Example 23-[4-(2-Morpholin-4-yl-2-oxo-ethyl)-3-oxo-piperazin-1-ylmethyl)-2-thiophen-2-yl-quinoline-4-carboxylicacid ((S)-1-cyclohexyl-ethyl)-amide

Following the general procedure described in Example 1d,{4-[4-((S)-1-Cyclohexyl-ethylcarbamoyl)-2-thiophen-yl-quinolin-3-ylmethyl]-2-oxo-piperazin-1-yl}-aceticacid (Example 1c) was coupled with morpholine to give the titlecompound. MS (m/z) 604.2 (M⁺), 1.97 min.

Example 33-[3-Oxo-4-(2-oxo-2-piperazin-1-yl-ethyl)-piperazin-1-ylmethyl)-2-thiophen-2-yl-quinoline-4-carboxylicacid ((S)-1-cyclohexyl-ethyl)-amide

Following the general procedure described in Example 1d,{4-[4-((S)-1-Cyclohexyl-ethylcarbamoyl)-2-thiophen-2-yl-quinolin-3-ylmethyl]-2-oxo-piperazin-1-yl}-aceticacid (Example 1c) was coupled with piperazine-1-carboxylic acidtert-butyl ester to give4-(2-{4-[4-((S)-1-cyclohexyl-ethylcarbamoyl)-2-thiophen-2-yl-quinolin-3-ylmethyl]-2-oxo-piperazin-1-yl}-ethanoyl)-piperazine-1-carboxlicacid tert-butyl ester. The crude compound was dissolved in 3 mL ofmethanol, stirred with 4N HCl in 1,4-dioxane (1 mL) for 1 hour. Themixture was concentrated to give the crude product which uponpurification via Reverse phase HPLC, eluting with acetonitrile/water(10/90, v/v to 90/10, v/v, over 10 min), gave the desired product (35mg, 30%). MS (m/z) 603.6 (M⁺), 1.63 min.

Example 43-(4-Carbamoylmethyl-3-oxo-piperazin-1-ylmethyl)-2-thiophen-2-yl-quinoline-4-carboxylicacid ((S)-1-cyclohexyl-ethyl)-amide

Following the general procedure described in Example 1d,{4-[4-((S)-1-Cyclohexyl-ethylcarbamoyl)-2-thiophen-2-yl-quinolin-3-ylmethyl]-2-oxo-piperazin-1-yl}-aceticacid (Example 1c) was coupled with ammonia to give the title compound(49%). MS (m/z) 534.2 (M⁺), 1.79 min.

Example 53-{4-[2-(4-Methyl-piperazin-1-yl)-2-oxo-ethyl]-3-oxo-piperazin-1-ylmethyl}-2-thiophen-2-yl-quinoline-4-carboxylicacid ((S)-1-cyclohexyl-ethyl)-amide

Following the general procedure described in Example 1d,{4-[4-((S)-1-Cyclohexyl-ethylcarbamoyl)-2-thiophen-2-yl-quinolin-3-ylmethyl]-2-oxo-piperazin-1-yl}-aceticacid (Example 1c) was coupled with N-methylpiperazine to give the titlecompound (16%). MS (m/z) 617.2 (M⁺), 1.62 min.

Example 63-[3-Oxo-4-(2-oxo-piperidin-1-yl-ethyl)-piperazin-1ylmethyl]-2-thiophen-2-yl-quinoline-4-carboxylicacid ((S)-1-cyclohexyl-ethyl)-amide

Following the general procedure described in Example 1d,{4-[4-((S)-1-Cyclohexyl-ethylcarbamoyl)-2-thiophen-2-yl-quinolin-3-ylmethyl]-2-oxo-piperazin-1-yl}-aceticacid (Example 1c) was coupled with piperidine to give the title compound(63%). MS (m/z) 602.0 (M⁺), 2.19 min.

Example 73-[3-Oxo-4-(2-oxo-pyrrolidin-1-yl-ethyl)-piperazin-1ylmethyl]-2-thiophen-2-yl-Quinoline-4-carboxylicacid (S)-1-cyclohexyl-ethyl)-amide

Following the general procedure described in Example 1d,{4-[4-((S)-1-Cyclohexyl-ethylcarbamoyl)-2-thiophen-2-yl-quinolin-3-ylmethyl]-2-oxo-piperazin-1-yl}-aceticacid (Example 1c) was coupled with pyrrolidine to give the titlecompound (43%). MS (m/z) 587.6 (M⁺), 2.07 min.

Example 83-[4-(3-Morpholin-4-yl-3-oxo-propyl)-3-oxo-piperazin-1-ylmethyl)-2-thiophen-2-yl-quinoline-4-carboxylicacid ((S)-1-cyclohexyl-ethyl)-amide 8a)3-{4-[4-((S)-1-Cyclohexyl-ethylcarbamoyl)-2-thiophen-2-yl-quinolin-3-ylmethyl]-2-oxo-piperazin-1-yl}-propionicacid

To a solution of3-(3-oxo-piperazin-1-ylmethyl)-2-thiophen-2-yl-quinoline-4-carboxylicacid ((S)-1-cyclohexyl-ethyl)-amide (Example 1c) (100 mg, 0.21 mmol) in5 mL of acetonitrile, was added potassium hydroxide (35 mg, 0.63 mmol),followed by ethyl acrylate (0.033 mL, 0.31 mmol). The mixture wasstirred at room temperature for 3 days, then concentrated. The residuewas acidified with 1N aqueous HCl and extracted with dichloromethane(2×). The organic phase was dried over Na₂SO₄, and concentrated to givethe crude material. This was used directly in the next step withoutfurther purification.

8b)3-[4-(3-Morpholin-4-yl-3-oxo-propyl)-3-oxo-piperazin-1-ylmethyl)-2-thiophen-2-yl-quinoline-4-carboxylicacid ((S)-1-cyclohexyl-ethyl)-amide

Following the general procedure described in Example 1d,3-{4-[4-((S)-1-Cyclohexyl-ethylcarbamoyl)-2-thiophen-2-yl-quinolin-3-ylmethyl]-2-oxo-piperazin-1-yl}-propionicacid (Example 8a) was coupled with morpholine to give the title compound(84%, two steps). MS (m/z) 618.4 (M⁺), 1.99 min.

Example 93-[4-(2-Morpholin-4-yl-2-oxo-ethyl)-2-oxo-piperazin-1-ylmethyl]-2-thiophen-2-ylquinoline-4-carboxylic acid ((S)-1-cyclohexyl-ethyl)-amide a)4-[4-((S)-1-Cyclohexyl-ethylcarbamoyl)-2-thiophen-2-yl-quinolin-3-ylmethyl]-3-oxo-piperazine-1-carboxylicacid tert-butyl ester

To a solution of 3-oxo-piperazine-1-carboxylic acid tert-butyl ester(320 mg, 1.6 mmol) in a mixture of DMF (10 mL) and DMSO (2 mL) at 0° C.,sodium hydride (60% in oil, 192 mg, 4.8 mmol) was added. The reactionmixture was stirred at 0° C. for 10 min and at room temperature for 30min. The mixture was re-cooled to 0° C. whereupon3-bromomethyl-2-thiophen-2-yl-quinoline-4-carboxylic acid((S)-1-cyclohexyl-ethyl)-amide (WO0244165) (731 mg, 1.6 mmol) was added.After the addition was complete, the reaction mixture was stirred atroom temperature for 4 hours then partitioned between ethyl acetate andbrine. The combined organic phase was washed with brine, dried (MgSO₄),filtered and concentrated. The resulting residue was purified via columnchromatography on silica gel using ethyl acetate:hexanes (1:1) as mobilephase to 616 mg of the title compound: LC-MS m/z 577.0 (M⁺).

b) 3-(2-Oxo-piperazin-1-ylmethyl)-2-thiophen-2-yl-quinoline-4-carboxylicacid ((S)-1-cyclohexyl-ethyl)-amide, HCl salt

HCl in dioxane (4.0M, 6.75 mL) was added to4-{4-[((S)-1-cyclohexyl-ethylamino)-methyl]-2-thiophen-2-yl-quinolin-3-ylmethyl}-3-oxo-piperazine-1-carboxylicacid tert-butyl ester (616 mg). The resulting reaction mixture wasstirred at room temperature for 3 hours. The solvent was evaporated togive the title compound (624 mg): LC-MS m/z 477.2 (M⁺).

c){4-[4-((S)-1-Cyclohexyl-ethylcarbamoyl)-2-thiophen-2-yl-quinolin-3-ylmethyl]-3-oxo-piperazin-1-yl}-aceticacid ethyl ester

To a solution of3-(2-oxo-piperazin-1-ylmethyl)-2-thiophen-2-yl-quinoline-4-carboxylicacid ((S)-1-cyclohexyl-ethyl)-amide, HCl salt (600 mg, 1.17 mmol) inacetonitrile (20 mL), N,N-diisopropyl ethylamine (151 mg, 3.51 mmol) andbromo-acetic acid ethyl ester (293 mg, 1.75 mmol) were added at roomtemperature. The reaction mixture was stirred at room temperature for 4hours. The solvent was removed under reduced pressure and the residuere-dissolved in ethyl acetate and washed with water. The combinedorganic phase was washed with brine, dried (MgSO₄), filtered andconcentrated to provide 600 mg of title compound: LC-MS m/z 563.2 (M⁺).

d){4-[4-((S)-1-Cyclohexyl-ethylcarbamoyl)-2-thiophen-2-yl-quinolin-3-ylmethyl]-3-oxo-piperazin-1-yl}-aceticacid

To a solution of{4-[4-((S)-1-cyclohexyl-ethylcarbamoyl)-2-thiophen-2-yl-quinolin-3-ylmethyl]-3-oxo-piperazin-1-yl}-aceticacid ethyl ester (600 mg, 1.06 mmol) in ethanol (20 ml), lithiumhydroxide (224 mg, 5.3 mmol) was added. The reaction mixture was stirredat room temperature for 16 hours. The solvent was removed under reducedpressure. Acetic acid (10%) was added to the residue until pH=4 followedby extraction with ethyl acetate. The combined organic phase was washedwith brine, dried (MgSO₄), filtered and concentrated to provide 700 mgof the title compound: LC-MS m/z 535.2 (M⁺).

e)3-[4-(2-Morpholin-4-yl-2-oxo-ethyl)-2-oxo-piperazin-1-ylmethyl]-2-thiophen-2-yl-quinoline-4-carboxylicacid ((S)-1-cyclohexyl-ethyl)-amide

Following the general procedure described in Example 1c){4-[4-((S)-1-Cyclohexyl-ethylcarbamoyl)-2-thiophen-2-yl-quinolin-3-ylmethyl]-3-oxo-piperazin-1-yl}-aceticacid (282 mg, 0.53 mmol) was coupled with morpholine (55 mg, 0.53 mmol)to give 140 mg of the title compound. LC-MS m/z 604.4 (M⁺).

Example 103-(4-Dimethylcarbamoylmethyl-2-oxo-piperazin-1-ylmethyl)-2-thiophen-2-yl-quinoline-4-carboxylicacid ((S)-1-cyclohexyl-ethyl)-amide

Following the general procedure described in Example 9,{4-[4-((S)-1-Cyclohexyl-ethylcarbamoyl)-2-thiophen-2-yl-quinolin-3-ylmethyl]-3-oxo-piperazin-1-yl}-aceticacid (286 mg, 0.53 mmol) was coupled with dimethylamine (2.0 M in THF,0.53 ml, 1.06 mmol) to give 84 mg of the title compound. LC-MS m/z 562.2(M⁺).

Example 116-Fluoro-3-[4-(2-morpholin-4-yl-2-oxo-ethyl)-3-oxo-piperazin-1-ylmethyl]-2-thiophen-2-yl-quinoline-4-carboxylicacid ((S)-1-cyclohexyl-ethyl)-amide 11a){4-[4-((S)-1-Cyclohexyl-ethylcarbamoyl)-6-fluoro-2-thiophen-2-yl-quinolin-3-ylmethyl]-2-oxo-piperazin-1-yl}-aceticacid

A solution of6-Fluoro-3-(3-oxo-piperazin-1-ylmethyl)-2-thiophen-2-yl-quinoline-4-carboxylicacid ((S)-1-cyclohexyl-ethyl)-amide (Prepared in a fashion analogous to{4-[4-((S)-1-Cyclohexyl-ethylcarbamoyl)-2-thiophen-2-yl-quinolin-3-ylmethyl]-2-oxo-piperazin-1-yl}-aceticacid—Example 1c) (35 mg, 0.0734 mmol) in DMF (0.5 mL) was mixed with NaH(5.3 mg, 60% in mineral oil, 0.22 mmol) at room temperature. Theresultant mixture was stirred for 3 minutes and mixed with bromo-aceticacid ethyl ester (8.1 μL, 0.0734 mmol). After stirring for 1 hr,purification via reverse phase HPLC afforded the title compound (36.5mg, 90%). MS (ES) m/z 553 (M+H)⁺.

11b)6-Fluoro-3-[4-(2-morpholin-4-yl-2-oxo-ethyl)-3-oxo-piperazin-1-ylmethyl]-2-thiophen-2-yl-quinoline-4-carboxylicacid ((S)-1-cyclohexyl-ethyl)-amide

A solution of{4-[4-((S)-1-Cyclohexyl-ethylcarbamoyl)-6-fluoro-2-thiophen-2-yl-quinolin-3-ylmethyl]-2-oxo-piperazin-1-yl}-aceticacid (23 mg, 0.0416 mmol) in DMF (0.5 mL) was mixed with morpholine (3.6μL, 0.0416 mmol), HBTU (15.8 mg, 0.0416 mmol) and 4-methyl-morpholine(8.9 μL, 8.09 mmol). After stirring for 1 hr, purication via reversephase HPLC afforded the title compound (20 mg, 77%). MS (ES) m/z 622(M+H)⁺.

Example 126-Fluoro-3-[3-oxo-4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperazin-1-ylmethyl]-2-thiophen-2-yl-quinoline-4-carboxylicacid ((S)-1-cyclohexyl-ethyl)-amide

The title compound was prepared from{4-[4-((S)-1-Cyclohexyl-ethylcarbamoyl)-6-fluoro-2-thiophen-2-yl-quinolin-3-ylmethyl]-2-oxo-piperazin-1-yl}-aceticacid and pyrrolidine in 58% yield by following the procedure of Example11b. MS (ES) m/z 606 (M+H)⁺.

Example 133-{4-[2-((R)-2-Hydroxymethyl-pyrrolidin-1-yl)-2-oxo-ethyl]-3-oxo-piperazin-1-ylmethyl}-2-thiophen-2-yl-quinoline-4-carboxylicacid ((S)-1-cyclohexyl-ethyl)-amide

Following the general procedure described in Example 1d,{4-[4-((S)-1-Cyclohexyl-ethylcarbamoyl)-2-thiophen-2-yl-quinolin-3-ylmethyl]-2-oxo-piperazin-1-yl}-aceticacid (Example 1c) was coupled with (R)-1-Pyrrolidin-2-yl-methanol togive the title compound (51%). MS (m/z) 618.2 (M⁺), 1.95 min.

Example 143-(4-{[(2,5-Dimethyl-2H-pyrazol-3ylmethyl)-carbamoyl]-methyl}-3-oxo-piperazin-1-ylmethyl)-2-thiophen-2-yl-quinoline-4-carboxylicacid ((S)-1-cyclohexyl-ethyl)-amide

Following the general procedure described in Example 1d,{4-[4-((S)-1-Cyclohexyl-ethylcarbamoyl)-2-thiophen-2-yl-quinolin-3-ylmethyl]-2-oxo-piperazin-1-yl}-aceticacid (Example 1c) was coupled withC-(2,5-dimethy-2H-pyrazol-3-yl)-methylamine to give the title compound(51%). MS (m/z) 642.4 (M⁺), 2.24 min.

Example 153-(4-{[(5-Methyl-1H-imidazol-2ylmethyl)-carbamoyl]-methyl}-3-oxo-piperazin-1-ylmethyl)-2-thiophen-2-yl-quinoline-4-carboxylicacid ((S)-1-cyclohexyl-ethyl)-amide

Following the general procedure described in Example 1d,{4-[4-((S)-1-Cyclohexyl-ethylcarbamoyl)-2-thiophen-2-yl-quinolin-3-ylmethyl]-2-oxo-piperazin-1-yl}-aceticacid (Example 1c) was coupled withC-(4-methy-1H-imidazol-2-yl)-methylamine to give the title compound(43%). MS (m/z) 628.4 (M⁺), 1.70 min.

Example 163-{4-[(Methyl-thiophen-2ylmethyl)-carbamoyl)-methyl}-3-oxo-piperazin-1-ylmethyl)-2-thiophen-2-yl-quinoline-4-carboxylicacid ((S)-1-cyclohexyl-ethyl)-amide

Following the general procedure described in Example 1d,{4-[4-((S)-1-Cyclohexyl-ethylcarbamoyl)-2-thiophen-2-yl-quinolin-3-ylmethyl]-2-oxo-piperazin-1-yl}-aceticacid (Example 1c) was coupled with methyl-thiophene-2-ylmethyl-amine togive the title compound (31%). MS (m/z) 644.2 (M⁺), 2.61 min.

1. A compound of formula (I)

wherein: R₁ is H or substituted or unsubstituted (C₁₋₆)alkyl; R₂ issubstituted or unsubstituted aryl, (C₃₋₇)cycloalkyl, or heterocycle; R₃is H or substituted or unsubstituted (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl, arylor heterocycle; A is NR₈ or O; R₈ is H or substituted or unsubstituted(C₁₋₆)alkyl; R₄ is substituted or unsubstituted heterocycle; R₅ is H orup to three substitutents independently selected from the listconsisting of alkyl, alkenyl, aryl, alkoxy, or a hydroxylatedderiviative thereof, hydroxy, halogen, nitro, cyano, carboxy,alkylcarboxy, alkylcarboxyalkyl, haloalkyl, amino or mono- ordialkylamino; or R₅ represents a bridging moiety which is arranged tobridge two adjacent ring atoms, wherein the bridging moiety comprisesalkyl or dioxyalkylene; R₆ is H or halo; R₇ is oxo; n is 1 to 4; or apharmaceutically acceptable salt thereof.
 2. A compound according toclaim 1 wherein R₁ is methyl.
 3. A compound according to claim 1 whereinR₂ is substituted or unsubstituted phenyl or cyclohexyl.
 4. A compoundaccording to claim 1 wherein R₃ or methyl or substituted orunsubstituted morpholino, piperizine, pyrrole, piperidine, thiophene,imidazole, or pyrazole.
 5. A compound according to claim 1 wherein R₈ isH or methyl.
 6. A compound according to claim 1 wherein R₄ issubstituted or unsubstituted 2-thienyl or 3-thienyl.
 7. A compoundaccording to claim 1 wherein R₅ is H or fluoro.
 8. A compound accordingto claim 1 wherein R₆ is H or fluoro.
 9. A compound according to claim 1which is:3-(4-Dimethylcarbamoylmethyl-3-oxo-piperazin-1-ylmethyl)-2-thiophen-2-yl-quinoline-4-carboxylicacid ((S)-1-cyclohexyl-ethyl)-amide,3-[4-(2-Morpholin-4-yl-2-oxo-ethyl)-3-oxo-piperazin-1-ylmethyl)-2-thiophen-2-yl-quinoline-4-carboxylicacid ((S)-1-cyclohexyl-ethyl)-amide,3-[3-Oxo-4-(2-oxo-2-piperazin-1-yl-ethyl)-piperazin-1-ylmethyl)-2-thiophen-2-yl-quinoline-4-carboxylicacid ((S)-1-cyclohexyl-ethyl)-amide,3-(4-Carbamoylmethyl-3-oxo-piperazin-1-ylmethyl)-2-thiophen-2-yl-quinoline-4-carboxylicacid ((S)-1-cyclohexyl-ethyl)-amide,3-{4-[2-(4-Methyl-piperazin-1-yl)-2-oxo-ethyl]-3-oxo-piperazin-1-ylmethyl}-2-thiophen-2-yl-quinoline-4-carboxylicacid ((S)-1-cyclohexyl-ethyl)-amide,3-[3-Oxo-4-(2-oxo-piperidin-1-yl-ethyl)-piperazin-1-ylmethyl]-2-thiophen-2-yl-quinoline-4-carboxylicacid ((S)-1-cyclohexyl-ethyl)-amide,3-[3-Oxo-4-(2-oxo-pyrrolidin-1-yl-ethyl)-piperazin-1-ylmethyl]-2-thiophen-2-yl-quinoline-4-carboxylicacid ((S)-1-cyclohexyl-ethyl)-amide,3-[4-(3-Morpholin-4-yl-3-oxo-propyl)-3-oxo-piperazin-1-ylmethyl)-2-thiophen-2-yl-quinoline-4-carboxylicacid ((S)-1-cyclohexyl-ethyl)-amide,3-[4-(2-Morpholin-4-yl-2-oxo-ethyl)-2-oxo-piperazin-1-ylmethyl]-2-thiophen-2-yl-quinoline-4-carboxylicacid ((S)-1-cyclohexyl-ethyl)-amide,3-(4-Dimethylcarbamoylmethyl-2-oxo-piperazin-1-ylmethyl)-2-thiophen-2-yl-quinoline-4-carboxylicacid ((S)-1-cyclohexyl-ethyl)-amide,6-Fluoro-3-[4-(2-morpholin-4-yl-2-oxo-ethyl)-3-oxo-piperazin-1-ylmethyl]-2-thiophen-2-yl-quinoline-4-carboxylicacid ((S)-1-cyclohexyl-ethyl)-amide,6-Fluoro-3-[3-oxo-4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperazin-1-ylmethyl]-2-thiophen-2-yl-quinoline-4-carboxylicacid ((S)-1-cyclohexyl-ethyl)-amide,3-{4-[2-((R)-2-Hydroxymethyl-pyrrolidin-1-yl)-2-oxo-ethyl]-3-oxo-piperazin-1-ylmethyl}-2-thiophen-2-yl-quinoline-4-carboxylicacid ((S)-1-cyclohexyl-ethyl)-amide,3-(4-{[(2,5-Dimethyl-2H-pyrazol-3ylmethyl)-carbamoyl)-methyl}-3-oxo-piperazin-1-ylmethyl)-2-thiophen-2-yl-quinoline-4-carboxylicacid ((S)-1-cyclohexyl-ethyl)-amide,3-(4-{[(5-Methyl-1H-imidazol-2ylmethyl)-carbamoyl]-methyl}-3-oxo-piperazin-1-ylmethyl)-2-thiophen-2-yl-quinoline-4-carboxylicacid ((S)-1-cyclohexyl-ethyl)-amide, and3-{4-[(Methyl-thiophen-2ylmethyl)-carbamoyl)-methyl}-3-oxo-piperazin-1-ylmethyl)-2-thiophen-2-yl-quinoline-4-carboxylicacid ((S)-1-cyclohexyl-ethyl)-amide, or a pharmaceutically acceptablesalt thereof.
 10. A process for the preparation of a compound of formula(I) according to claim 1 or a salt thereof and/or a solvate thereof,which process comprises reacting a compound of formula (II) or an activederivative thereof:

wherein R′₄, R′₅, R′₆ and X′ are R₄, R₅, R₆ and X respectively ashereinbefore defined in relation to formula (I) or a group convertibleto R₄, R₅, R₆ and X respectively; with a compound of formula (III):

wherein R′₁ and R′₂, are R₁ and R₂ as defined for formula (I) or a groupor atom convertible to R₁ and R₂ respectively; to form a compound offormula (Ic):

wherein R′₁, R′₂, X′, R′₄, R′₅ and R′₆ are as defined above, andthereafter carrying out one or more of the following optional steps: (i)converting any one of R₁₁, R₁₂, X′, R₁₄, R′₅ and R₁₆ to R₁, R₂, X, R₄,R₅ and R₆ respectively as required, to obtain a compound of formula (I);(ii) converting a compound of formula (I) into another compound offormula (I); and (iii) preparing a salt of the compound of formula (I)and/or a solvate thereof.
 11. A pharmaceutical composition whichcomprises a compound according to claim 1 and a pharmaceuticallyacceptable carrier.
 12. A method of treating respiratory diseases inmammals, which comprises administering an effective amount of a compoundaccording to claim 1.